Skeletal muscle is a mechanically and energetically active organ, supporting vital processes such as respiration and locomotion, and is a major site of glucose and lipid metabolism. Therefore, maintaining proper muscle mass and function is critical. Muscle incurs damage due to a variety of insults such as use, disuse, aging and pathology. While skeletal muscle does not undergo rapid turn-over under normal conditions, upon being damaged, it is capable of executing a robust regenerative response through mobilization of its resident progenitor cells, the satellite cells (Moss FP, Leblond CP, Anat Rec 170:421-436 (1970); Schultz E, Gibson MC, Champion T, J Exp Zool 206(3):451-6 (1978); Snow MH, Cell Tissue Res 186(3):535-40 (1978)). The self-renewal and differentiation capacity of the satellite cells have alluded to the archetypic “stemness,” but their fate seems largely committed (Sinanan ACM, Buxton PG, Lewis MP, Bio Cell 98:203-214 (2006); Beauchamp JR et al., J Cell Biol 151:1221-1234 (2000); Starkey JD et al., J Histochem Cytochem 59(1):33-46 (2011)). In an adult, satellite cells comprise less than 5% of total nuclei on a myofiber; nevertheless, based on their proliferation kinetics and capacity, this is sufficient to regenerate an entire muscle (Schmalbruch H, Hellhammer U, Anat Rec 189:169-176 (1977); Kelly AM, Dev Bio 65(1): 1-10 (1978); Gibson MC, Schultz E, Anat Rec 202(3):329-337 (1982); Bischoff R in Myology, Vol 1, eds Engel AG, Franzini-Armstrong C (McGraw-Hill, Inc., New York), (1994); Zammit PS et al., Exp Cell Res 281:39-49 (2002)).
Upon injury, skeletal muscle responds to damage in three distinct but overlapping phases: degeneration; regeneration; and finally remodeling (Charge SBP, Rudnicki MA, Physiol Rev 84:209-238 (2004)). Immediately following the injury, inflammatory cells are recruited to the injury site to promote degeneration of the damaged tissue through necrosis and phagocytosis (Tidball JG, Am J Physiol Regul Integr Comp Physio 288:R345-353 (2005); McLennan IS, J Anat 188:17-28 (1996); Pimorady-Esfahani A, Grounds MD, McMenamin PG, Muscle Nerve 20:158-166 (1997); Vierck J et al., Cell Bio Int 24:263-272 (2000); Arnold L et al., J Exp Med 204(5):1057-1069 (2007)). The subsequent regenerative phase is characterized by mobilization of satellite cells, whereby the progenitor cells proliferate, differentiate and fuse to each other or to the existing fibers to regenerate the muscle (Zammit PS in Skeletal muscle repair and regeneration, eds Schiaffino S, Partridge T (Springer, Dordrecht (2008)). Finally, the contractile proteins are reassembled and function is restored during the remodeling phase.